a thorough transurethral resection of the bladder (TURB),
since several studies now indicate that a radical TURB
predicts a more favorable prognosis after chemoradiother-
. Clearly, the not infrequent toxicity of the
chemoradiotherapy and the need for close bladder surveil-
lance after treatment, considering the 1 in 5 requirement of
later salvage cystectomy, warrant the involvement of
urologists in these strategies.
Conflicts of interest:
The author has nothing to disclose.
Shelley MD, Wilt TJ, Barber J, Mason MD. A meta-analysis of
randomised trials suggests a survival beneFt for combined radio-
therapy and radical cystectomy compared with radical radiothera-
py for invasive bladder cancer: are these data relevant to modern
practice? Clin Oncol (R Coll Radiol) 2004;16:166–71.
Plataniotis GA, Dale RG. Radio-chemotherapy for bladder cancer:
contribution of chemotherapy on local control. World J Radiol
James ND, Hussain SA, Hall E, et al. Radiotherapy with or without
chemotherapy in muscle-invasive bladder cancer. N Engl J Med
Coen JJ, Paly JJ, Niemierko A, et al. Nomograms predicting response
to therapy and outcomes after bladder-preserving trimodality
therapy for muscle-invasive bladder cancer. Int J Radiat Oncol Biol
Phys 2013;86:311–6.
Henk van der Poel
Department of Urology, Netherlands Cancer Institute, Amsterdam,
The Netherlands
*Department of Urology, Netherlands Cancer Institute, Plesmanlaan 121,
1066 CX Amsterdam, The Netherlands.
E-mail addresses:
Re: Advanced Paternal Age and Mortality of Offspring
Under Five Years of Age: A Register-based Cohort Study
Urhoj SK, Jespersen LN, Nissen M, Mortensen LH, Nybo
Anderson AM
Hum Reprod 2014;29:343–50
Experts’ summary:
Recently, Urhoj et al. completed a population-based register
study of children born in Denmark from 1978 to 2004. A total
of approximately 1.5 million newborns were followed for a
minimum of 5 yr (until December 2009). Tracked using a
unique civil identification number, children were linked to
numerous registries, with data adjusted for maternal age,
parity, and education level. The authors noted that when
children aged 1–5 yr were examined, the hazard ratio (ie,
the mortality risk over the duration of the study period) for
children born to fathers aged 40–44 yr compared to those aged
45 yr rose to 1.24 (95% confidence interval [CI], 1.00–1.53)
and 1.65 (95% CI, 1.24–2.18), respectively. This excess risk for
mortality was primarily due to death from congenital mal-
formations (eg, respiratory and musculoskeletal), malignan-
cies, and external reasons (eg, injury, poisoning); however, no
significant differences between these causes were identified.
While the overall risk for mortality for children aged
low, the association between the negative effects of advanced
paternal age (APA) and child health remains to be explained.
Experts’ comments:
This study adds to the expanding evidence that APA at the time
of birthcontributesto increases ininfant mortality, with similar
findings previously reportedfor childrenuptoage18yr
is currently of interest given that couples are routinely delaying
conception due to career aspirations, with some considering in
vitro fertilization (IV±) as a
reproductive security blanket
. Indeed,
the numberofwomengivingbirthatage
35yrisatthe highest
level since 1967. In Europe, the average age of married fathers
has gradually increased and men of APA now account for 15%
more births than they did 10 yr ago
When patients present to the urologist for an opinion on
APA, the physician should be aware of several important
facts regarding reproductive health. Currently, there is no
universal definition of APA. In the literature, the most
frequently cited age is 40 yr; however, paternal information
is often missing from birth certificates, with the age of the
father not reported in 14% of all births. Spermatogenesis,
testicular function, and semen quality (ie, volume, motility,
and concentration) decline with age. While these changes
alone do not directly prove that men of APA have a lower
chance of conceiving, other studies have found that the time
to achieve pregnancy, as well as the rates of conceptions, are
adversely affected in APA, regardless of whether they occur
naturally or via IV±
The most recently debated topics, including the paper by
Urhoj et al., focus on the effects of APA on offspring health.
While increased risks to offspring of advanced maternal age
are well documented, the paternal age at which offspring
are affected is unknown, making counseling difficult.
Studies have noted that the offspring of men of APA are
2.2 times more likely to have autism (age
50 yr
schizophrenia (age
55 yr; odds ratio, 3.8), and bipolar
disorder (age
55 yr, 1.37 times
). The most character-
ized contribution of APA to a genetic condition occurs in
achondroplasia, a common form of dwarfism (general
population occurrence of 1:15 000 vs 1:1875 if
50 yr of
These concerns were then elucidated in a study
published in
by Kong et al.
showing that APA
contributes to an increased number of genetic mutations
inherited by offspring. These reports have led younger men
to question whether they should be banking sperm now,
while young, to prevent the risks associated with APA. No
guidelines are available to direct counseling with regard to
the effectiveness and safety of freshly ejaculated sperm
compared to frozen samples. However, with cryopreserved
sperm, conception can only be achieved either by intra-
uterine insemination or IV±—a decision that carries with it
other inherent risks
EUROPEAN UROLOGY 65 (2014) 1218–1223